Multi-well apparatus

ABSTRACT

A multi-well assembly ( 10 ) comprises a multi-well block ( 12 ) and a guide plate ( 14 ). The multi-well block ( 12 ) has a plurality of wells ( 18 ) each with a fluid-impermeable bottom surface ( 22 ). The guide plate ( 14 ) has a plurality of fluid passageways ( 34 ) corresponding to the wells ( 18 ) of the multi-well block ( 12 ). The guide plate ( 14 ) is configured to establish fluid communication between each well ( 18 ) and an associated fluid passageway ( 34 ) when the guide plate ( 14 ) is aligned with the multi-well block ( 12 ).

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No.60/274,262, filed on Mar. 8, 2001.

FIELD

The present invention concerns multi-well apparatus, typically usefulfor chemical, biological and biochemical analysis.

BACKGROUND

In recent years, various areas of research have demanded cost-effectiveassays and reactions of diminishing scale, increasing efficiency andaccuracy, with high-throughput capacity. Multi-well devices withmultiple individual wells, such as multi-well plates or multi-wellblocks, are some of the most commonly used tools to carry out suchreactions and assays. A variety of multi-well arrangements, constructedaccording to standardized formats, are commercially available. Forexample, a multi-well device having ninety-six depressions or wellsarranged in a 12×8 array is a commonly used arrangement. Conventionalmulti-well devices may have wells with either fluid-impervious bottomsurfaces to retain matter in the wells or open bottoms, in which case areceptacle plate may be placed underneath the multi-well device tocollect matter flowing from the wells.

Test plates for numerous applications are well-known in the art. Forexample, test plates are known for use in culturing tissue samples.Other forms of test plates are adapted for carrying out chemicalreactions or for use in micro-chromatography.

For applications requiring filtration, respective filters may bepositioned in the wells of a multi-well device. In such applications,vacuum or pressure may be applied to facilitate filtration of fluidsamples in the wells of the device. Following filtration, the fluids maybe collected in individual containers or wells of a receptacle plate.

Despite these prior inventions, there exists a continuing need for newand improved multi-well apparatus and methods for their use.

SUMMARY

The present invention is directed toward aspects and features of amulti-well assembly for use in, for example, chemical, biological, andbiochemical analysis.

A multi-well assembly according to one representative embodimentcomprises a multi-well block and a guide plate. The multi-well block hasa plurality of wells, with each well having a fluid-impermeable bottomsurface. The guide plate defines a plurality of fluid passagewayscorresponding to the wells of the multi-well block. The guide plate isconfigured such that, whenever the guide plate is registered with themulti-well block, fluid communication is established between each welland an associated fluid passageway.

In an illustrated embodiment, the guide plate has a plurality ofprojections corresponding to the wells of multi-well block. Theprojections are configured to perforate the bottom surfaces ofrespective wells whenever the guide plate is registered with themulti-well block to allow the contents (e.g., chemicals) of each well toflow outwardly, such as under the force of gravity, through theperforated bottom surfaces of the wells and into respective fluidpassageways. The fluid passageways in a disclosed embodiment comprisechannels extending substantially longitudinally through the guide plateand each projection.

The multi-well assembly also may include a second multi-well block (alsotermed a “receptacle” block) for receiving or collecting the contents ofthe wells of the multi-well block. The receptacle block in particularembodiments has a plurality of wells, each of which corresponds to arespective fluid passageway of the guide plate. Thus, whenever thereceptacle block is registered with the guide plate and the multi-wellblock, a fluid path is defined between each well of the multi-wellblock, a respective fluid passageway of the guide plate, and arespective well of the receptacle block. An optional cover may beprovided for covering the open tops of the wells of the multi-wellblock.

According to another representative embodiment, a multi-well assemblycomprises a first plate and a second plate. The first plate has aplurality of wells. The second plate has a plurality of upwardlyextending fluid conduits, each of which is adapted to receive thecontents of a well whenever the first plate is registered with thesecond plate. In addition, the fluid conduits may be configured suchthat, whenever the first plate is registered with the second plate, eachfluid conduit extends upwardly into the lower portion of a respectivewell to receive fluid therefrom. In particular embodiments, the fluidconduits comprise projections formed with substantially longitudinallyextending passageways. The second plate also may be provided with anupwardly extending wall circumscribing each fluid conduit. The walls areconfigured such that, whenever the first plate is registered with thesecond plate, each wall matingly fits around the lower portion of arespective well to minimize cross-contamination between adjacent wells.

In another representative embodiment, a multi-well device includes aplurality of wells, with each well having a fluid-impervious lowersurface. A guide tray has a plurality of fluid passageways thatcorrespond to the wells of the multi-well device. The guide tray alsohas means for fluidly connecting each fluid passageway with acorresponding well whenever the guide tray is registered with themulti-well device.

According to yet another representative embodiment, a guide plate foruse with a multi-well device comprises a body having upper and lowermajor surfaces. A plurality of projections depend from the upper majorsurface and a plurality of outlet spouts depend from the lower majorsurface below the projections. Extending through each projection andoutlet spout is a fluid passageway or channel. In a disclosedembodiment, an upwardly extending wall surrounds each projection and isconfigured to matingly fit around the lower portion of a well of themulti-well device whenever the guide plate is registered with themulti-well device. In addition, each projection may be formed with acutting surface that is configured to perforate the bottom surface of awell whenever the guide plate is registered with the multi-well device.

According to another representative embodiment, a guide plate for usewith a multi-well device comprises a body having first and second majorsurfaces. A plurality of projections depend from one of the first andsecond major surfaces. Each projection is configured to perforate thebottom surface of a well of the multi-well device whenever the guideplate is registered with the multi-well device. In particularembodiments, the projections are shaped in the form of an ungula (i.e.,a cylindrical or conical section formed by intersecting a cylinder orcone with one or more planes oblique to its base) and may be formed witha longitudinally extending channel.

In another representative embodiment, a method of carrying out multiplechemical reactions comprises providing a multi-well device having aplurality of wells with fluid-impervious bottom surfaces and a guideplate defining a plurality of passageways corresponding to the wells.Reagents for the chemical reactions may be introduced into the wells ofthe multi-well device. Upon completion of the chemical reactions, theguide plate may be registered with the multi-well device so that thebottom of each well is in flow-through communication with a passagewayin the guide plate. Thus, the products of the chemical reactions arepermitted to flow through the passageways and, if a receptacle plate isprovided, into corresponding wells of the receptacle plate.

These and other features of the invention will be more fully appreciatedwhen the following detailed description of the invention is read inconjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a multi-well assembly, according to oneembodiment, shown with a portion of the upper multi-well block brokenaway to show the upper surface of the guide plate, and with a portion ofthe guide plate broken away to show the wells of the lower multi-wellblock.

FIG. 2 is a side elevation view of the upper multi-well block of themulti-well assembly of FIG. 1, shown with a cover covering the open topsof the wells.

FIG. 3 is a perspective, sectional view of the upper multi-well block ofFIG. 1.

FIG. 4 is a bottom perspective view of the upper multi-well block ofFIG. 1.

FIG. 5 is a vertical section of the multi-well assembly of FIG. 1, shownwith a cover installed on the upper multi-well block and filterspositioned in each well.

FIG. 6 is a top perspective view of the guide plate of the multi-wellassembly of FIG. 1.

FIG. 7 is an enlarged perspective view of a portion of the guide plateshown partially in section.

FIG. 8 is an enlarged perspective view of a portion of the uppermulti-well block, shown partially in section, and a portion of the guideplate, shown partially in section, in which the wells of the uppermulti-well block are registered with corresponding fluid conduits of theguide plate.

FIG. 9 is a perspective view of the cover of FIG. 2.

DETAILED DESCRIPTION

Referring initially to FIG. 1, there is shown a multi-well assembly,indicated generally at 10, according one embodiment. Generally, theassembly 10 comprises a first multi-well block 12, a guide plate, ortray, 14 situated below the first multi-well block 12, and a secondmulti-well block 16 (also termed a “receptacle block”) situated belowthe guide plate 14. In use, chemical or biological matter is introducedinto the first multi-well block 12 for carrying out any of variouschemical, biological, and biochemical reactions and processes. Thesecond multi-well block 16 serves as a receptacle block for receivingchemical or biological matter from the first multi-well block 12, asdescribed in greater detail below.

Referring also to FIGS. 2-4, the first multi-well block 12 in theillustrated configuration has, as its name suggests, a generallyrectangular block-like shape and supports a 8×12 array of verticallydisposed, elongated wells, or cavities, 18. Such a 96-well array, withspecific (i.e., 9 mm) center-to-center spacing is a standardconfiguration for many commercially available multi-well test plates.The overall dimensional area of the first multi-well block 12, as wellas the guide plate 14 and the second multi-well block 16, provide for afootprint of the same size as a standard 96-well plate to permit usewith standard equipment holders, well washers, and the like.

Although in the illustrated embodiment the first multi-well block 12 isshown as having a generally block-like shape, the first multi-well block12 may be generally cylindrical in shape or have any of various othergeometric shapes. In addition, any number of wells 18 and anyarrangement of wells 18 may be used. For example, without limitation,other possible arrays of wells 18 include a 4×6 array and a 6×8 array.Although less desirable, in other embodiments, the first multi-wellblock 12 may support wells 18 that are not arranged in an ordered array.In still other embodiments, wells that are substantially shallower indepth than those of the illustrated embodiment may be used, in whichcase the first multi-well block 12 will have more of a plate-likeconfiguration, rather than the illustrated block-like shape. The wells18 may be configured to support volumes, for example, from about 100 μLto several mL per well, although wells having a larger or smallervolumetric capacity also may be used. In working embodiments, the wells18 are configured to hold about 2 mL to 3 mL per well.

The illustrated wells 18 have open tops 20 (FIGS. 1 and 3) andfluid-impermeable barriers 22 (FIGS. 3 and 4) that serve as bottomsurfaces for the wells 18. As best shown in FIGS. 3 and 5, each well 18has a generally rectangular (in the vertical direction) upper portion24, a cylindrical intermediate portion 26, and a cylindrical lowerportion 44. As shown, the upper portion 24 and lower portion 44 of eachwell 18 may be slightly tapered so that their cross-sectional profileexhibits decreasing width from top to bottom. The lower end of eachlower potion 44 is covered or sealed by the respective fluid barrier 22(FIGS. 2 and 4). In addition, as shown in FIGS. 3 and 5, the upperportion 24 of each well 18 may be formed with a curved bottom surface 28to prevent the contents of the well 18 from settling in the upperportion 24. In alternative embodiments, the well 18 may have any ofvarious other configurations. For example, an upper portion 24 may havea circular transverse cross-section or square-shaped transversecross-section with rounded corners. Alternatively, the wells 18 may beprovided with a constant cross-sectional shape along their entirelengths.

In addition, in still other embodiments, the barriers 22 may bedisplaced upward from the bottom edges of the lower portions 44. Forexample, the barriers 22 may be positioned within the intermediateportions 26 or the lower portions 44 of the wells 18. In any event, thebarriers 22 serve to retain matter (e.g., chemicals) introduced into therespective wells 18.

The barriers 22 desirably are about 0.005 to 0.015 inch thick, with0.010 inch being a specific example, although thinner or thickerbarriers 22 can be used. In other embodiments, the barriers 22 may havea variable thickness. For example, a barrier 22 may have a convex shapeso that its thickness is greatest at its center, or alternatively, aconcave shape so that its thickness is greatest at its periphery.

Referring to FIGS. 2, 5, and 9, an optional cover or lid 60 may beprovided for covering the open tops 20 of the wells 18. The cover 60 inthe configuration shown comprises a fluid-impermeable top portion 62 andlegs 64 that extend downwardly from opposing sides of the top portion62. The bottom of each leg 64 forms an inwardly extending latch 66 thatis dimensioned to fit within a corresponding notch 58 defined in a sideof the first multi-well block 12 (FIGS. 2 and 5). The legs 62 desirablyare made from a semi-flexible material to permit slight bending orflexing of the legs 62 when installing or removing the cover 60. Asealing member, such as a flat gasket (not shown), may be positionedbetween the open tops 20 and the cover 60 to ensure a fluid-tight seal.To remove the cover 62, the bottom ends of legs 64 are pulled away fromthe sides of the multi-well block 12 until the latch portions 66 areremoved from their associated notches 58, at which point the cover 62can be lifted away from the multi-well block 12.

Referring again to FIG. 1, the second multi-well block 16, like thefirst multi-well block 12, has an ordered array of wells 48, eachcorresponding to a respective well 18 of the first multi-well block 12.The guide plate 14 is configured to direct the flow of matter from thewells 18 of the first multi-well block 12 to corresponding wells 48 ofthe second multi-well block 16, as described below. In the illustratedembodiment, the second multi-well block 16 has the same construction asthe first multi-well block 12, however, this is not a requirement. Forexample, if the first multi-well block 12 and the guide plate 14 conformto a standardized format, such as the illustrated 96-well format, anysuitable commercially available receptacle block may be used in lieu ofthe illustrated second multi-well block 16.

Referring to FIGS. 5-8, the guide plate 14, in the illustratedconfiguration, comprises a body 38 having an upper major surface 40 anda lower major surface 42. The guide plate 14 has an ordered array ofupwardly extending fluid conduits in the form of projections 32, each ofwhich corresponds to a respective well 18 of the first multi-well block12. The guide plate 14 also may have an ordered array of downwardlyextending outlet spouts 50 located below respective projections 32. Theguide plate 14 is formed with respective bores, or channels, 34extending through each projection 32 and outlet spout 50.

The projections 32 are configured to perforate the respective barriers22 to allow the contents of each well 18 to flow outwardly therefromwhenever guide plate 14 is registered with the first multi-well block 12(as shown in FIGS. 5 and 8). As used herein, to “register” the guideplate 14 with the first multi-well block 12 means to align eachprojection 32 with the respective barrier 22 of a corresponding well 18and to press together the guide plate 14 and the first multi-well block12 until the projections 32 extend into the respective lower portions 44of the wells 18. Likewise, the second multi-well block 16 can beregistered with the guide plate 14 by aligning the open tops of thewells 48 with corresponding outlet spouts 50 of the guide plate 14 andpressing the guide plate 14 and the second multi-well block 16 togetherso that the outlet spouts 50 extend into the respective wells 48 (FIG.5).

As best shown in FIG. 7, the shape of each projection 32 in theillustrated embodiment is that of a cylindrical section formed byintersecting a cylinder with two planes oblique to the base of thecylinder in the manner shown. Thus, two flat, upwardly angled surfaces54 a, 54 b are provided that converge at the top, or crest, of theprojection 32 to form a cutting edge 56. The cutting edge 56 ispositioned to cut through a respective barrier 22 whenever the guideplate 14 and the first multi-well block 12 are pressed together. Otherforms for the projections 32 alternatively may be used. For example, theprojections 32 may be shaped in the form of a cone, a cylinder, or anyvariation thereof, and may or may not be provided with a cutting edge,such as shown in FIG. 7, to facilitate perforation of the barriers 22.

In alternative embodiments, the barriers 22 may be coupled to the lowerportions 44 of the wells 18 in a manner that allows the barriers to beremoved from sealing the bottom of their respective wells 18 withoutbeing perforated or otherwise damaged whenever the guide plate 14 isregistered with the first multi-well block 12. For example, a barrier 22may be hingedly connected to a lower portion 44 such that the barrier 22remains in a normally closed position for retaining the contents of thewell 18 whenever the first multi-well block 12 is not registered withthe guide plate 14. The hinged barrier 22 is caused to move to an openposition by a respective projection 32 to permit the contents of thewell 18 to escape therefrom whenever the first multi-well block 12 isregistered with the guide plate 14. The barrier 22 in this configurationmay be biased toward its normally closed position so that itautomatically closes or seals the lower portion 44 whenever the guideplate 14 is detached from the first multi-well block 12.

In another embodiment, a barrier 22 may be configured such that it isnormally biased in a closed position and is caused to move upwardlythrough a lower portion 44 by a respective projection 32 whenever thefirst multi-well block 12 is registered with the guide plate 14. In thisconfiguration, the lower portion 44 is tapered from top to bottom sothat an opening is created between the periphery of the barrier 22 andthe inner surface of the lower portion 44 as the barrier is moved in anupward direction by the respective projection 32.

In the embodiment shown in FIGS. 5-8, each projection 32 iscircumscribed by an upper wall 36 depending from the upper major surface40 of the guide plate 14. Each outlet spout 50 is similarlycircumscribed by a lower wall 52 depending form the lower major surface42. As shown in FIGS. 5 and 8, whenever the guide plate 14 is registeredwith the first multi-well block 12, each upper wall 36 of the guideplate 14 matingly fits around the lower portion 44 of a correspondingwell 18. This provides for a substantially fluid-tight passagewayextending between each well 18 and corresponding channel 34 tosubstantially reduce cross-contamination between adjacent wells 18. Inaddition, each lower wall 52 is dimensioned to fit within an open top 46of a corresponding well 48 of the second multi-well block 16. Thus,whenever the first multi-well block 12, the guide plate 14, and thesecond multi-well block 16 are assembled in the manner shown in FIG. 5,the contents of each well 18 of the multi-well block 12 are allowed toflow through the channels 34 of the guide plate 14 into correspondingwells 48 of the receptacle block 16.

Guide-plate and projection configurations other than the illustratedconfigurations also may be used. For example, in alternativeembodiments, one or more channels may be formed in the guide plate 14 inthe space between each projection 32 and its respective upper wall 36,rather than through the projections 32 themselves, to permit thecontents of the wells 18 to flow through the guide plate 14 whenever theguide plate 14 is registered with the first multi-well block 12. Instill other embodiments, the upper walls 36 are dimensioned to beinserted into respective lower portions 44 of the wells 18.

As shown in FIG. 5, optional filters 30 may be positioned within thewells 18 of the first multi-well block 12 to filter chemicals or othermatter introduced into the wells 18. Alternatively, filters (not shown)can be positioned in the channels 34 of the guide plate 14 and/or in thewells 48 of the second multi-well block 16. The filters 30 may compriseany suitable material, such as, for example, polypropylene,polyethylene, glass fiber, and the like.

The first multi-well block 12, the guide plate 14, the second multi-wellblock 16, and the cover 60 desirably are formed of a substantiallyrigid, water-insoluble, fluid-impervious material that is chemicallynon-reactive with the matter to be introduced into the multi-wellassembly 10. The term “substantially rigid” as used herein is intendedto mean that the material will resist deformation or warping under lightmechanical or thermal load. Suitable materials include, withoutlimitation, polystyrene, polyethylene, polypropylene, polyvinylidinechloride, polytetrafluoroethylene (PTFE), polyvinyledenefluoride (PVDF),glass-impregnated plastics, and stainless steel, among others. Inworking embodiments, polypropylene is used because it is easily amenableto varying temperature and pressure conditions, and is easy tofabricate.

The first multi-well block 12, the guide plate 14, the second multi-wellblock 16, and the cover 60 may be formed by any suitable method. Forexample, using conventional injection-molding techniques, each componentof the assembly 10 (i.e., the first multi-well block 12, the guide plate14, the second multi-well block 16, and the cover 60) can be formed as aunitary structure. In an alternative approach, various parts of eachcomponent may be formed and bonded together using conventionalthermal-bonding techniques. For example, the wells 18 and/or thebarriers 22 can be separately formed and subsequently thermally bondedtogether to form the first multi-well block 12.

The multi-well assembly 10 may be used in any of various chemical,biological, and biochemical reactions and processes such as, withoutlimitation, solution-phase or solid-phase chemical synthesis andreactions, protein-derivitization assays, protein-caption assays,biotinylation and fluorescence labeling assays, magnetic separationassays, chromatography, and culturing of microorganisms, among others.The processes in the assembly 10 may be carried out at room temperature,below room temperature, or above room temperature. In addition, theassembly 10 supports multiple simultaneous reactions.

In using the multi-well assembly 10 for, for example, carrying outmultiple chemical reactions, reagents are introduced into the wells 18of the first multi-well block 12, using, for example, a multi-channelpipette. In this manner, the first multi-well block 12 serves as a“reaction block” for carrying out the multiple chemical reactions. Aspreviously mentioned, the barriers 22 serve to retain the reagents inthe wells 18 during the reaction step. If desired, the cover 60 may beplaced on the first multi-well block 12 to prevent the escape of gasesthrough the open tops 20 of the wells 18 as the reactions occur, and/orto prevent contamination or cross-contamination of the reactions.

Upon completion of the reaction step, the bottom of each well 18 ismated and coaxially aligned with a respective upper wall 36 of the guideplate 14, and each well 48 of the second multi-well (receptacle) block16 is mated and aligned with a respective lower wall 52 of the guideplate 14. The first multi-well block 12, the guide plate 14, and thereceptacle block 16 may then be placed in a conventional pressingapparatus (not shown). The pressing apparatus is operated to press theassembly together to cause the projections 32 to perforate therespective barriers 22, thereby allowing the reaction products in eachwell 18 to flow through the channels 34 of the guide plate 14 and intothe respective wells 48 of the receptacle block 16 for analysis and/orstorage.

In specific working embodiments, the assembly 10 is configured such thatabout 5 lb to 15 lb of force per well 18 during pressing is sufficientto cause the projections 32 to perforate the barriers 22, although thisis not a requirement. In other embodiments, the assembly 10 may beconfigured to allow a user to register the first multi-well block 12,the guide plate 14, and the receptacle block 16 without the use of apressing apparatus.

After pressing, conventional techniques may be used to facilitateremoval of the contents of the wells 18. For example, the assembly 10may be centrifuged, or a pressure differential may be created across theassembly 10, as well known in the art. A pressure differential may becreated by, for example, applying positive pressure from acompressed-gas source (e.g., compressed air) to the wells 18 of thefirst multi-well block 12 or, alternatively, applying a vacuum to thewells 48 of the receptacle block 16.

After the reaction products are removed from the receptacle block 16,the assembly 10 may be cleaned and re-used in another process. Ifdesired, the bottom of the wells 18 may be re-sealed by, for example,welding a mat of suitable material (e.g., polypropylene) to the bottomof the wells 18. Otherwise, the first multi-well block 12 may be used asis, that is, without any barriers 22 in place to retain matterintroduced into the wells 18.

In addition, in other methods of use, after executing a first reactionstep, the receptacle block 16 may be used to perform a subsequentreaction or processing step, and additional chemicals or reagents may beintroduced into the wells 48. Thereafter, the receptacle block 16 can beregistered with another guide plate 14 and receptacle block 16 in themanner described above. In this manner, the receptacle block 16 is usedas a reaction block in the subsequent reaction or processing step.

The invention has been described with respect to particular embodimentsand modes of action for illustrative purposes only. The presentinvention may be subject to many modifications and changes withoutdeparting from the spirit or essential characteristics thereof. Wetherefore claim as our invention all such modifications as come withinthe scope of the following claims.

1. A method of carrying out multiple chemical reactions, the methodcomprising: providing a multi-well device comprising a plurality ofwells having fluid-impervious bottom surfaces; providing a guide platedefining a plurality of passageways corresponding to the wells;introducing reagents into the wells to initiate respective chemicalreactions in the wells; and registering the guide plate with themulti-well device so that each well is in flow-through communicationwith a respective passageway to permit products of the respectivechemical reactions to flow through the passageways, wherein the guideplate has a plurality of upwardly extending projections that open thefluid-impervious bottom surfaces of the plurality of wells whenever theguide plate is registered with the multi-well device, and whereinregistering the guide plate with the multi-well device comprisespressing the guide plate and the multi-well device together using apressing apparatus.
 2. The method of claim 1, further comprisingregistering a multi-well receptacle plate comprising a plurality ofwells with the guide plate to collect the products of the chemicalreactions flowing from the passageways.
 3. The method of claim 1,further comprising providing respective filters in the wells forfiltering the reagents.
 4. The method of claim 1, further comprisingcreating a pressure differential across the passageways to facilitatethe flow of the respective products of the respective chemical reactionsthrough the passageways.